Total synthesis of haplomintrins A and B and studies on enantioselective quinone Diels-Alder reactions

天然产物(次生代谢物)的全合成仍然是有机化学的一个持续挑战和重要部分，因为天然产物及其衍生物经常可用于识别新药或候选药物。为了完成大多数复杂的目标框架的合成，人们通常依赖于成熟的反应和方法。然而，为了解决潜在的合成困难或绕过现有方法的缺乏，必须开发新的方法。植物次生代谢物的一大类是萜类化合物，其中一些还具有显著的生物活性。2015年，Lou等人。报道了从中国地钱草中发现的两个新的拉布丹烷型二萜类化合物，单环内酯A和单环内酯B。本研究方案的主要目标是首次实现单链内酯A和B的对映选择性全合成。在这一思路下，计划利用文献中已知的手性催化剂进行对映体选择性的苯二酚Diels-Alder反应作为关键步骤。此外，还应测试中田型β-酮酰亚胺是否能够改进铜双(恶唑啉)络合物的手性诱导，特别是如果已知的手性催化剂体系在这一具有挑战性的醌-迪尔斯-阿尔德反应中失败的话。有了Diels-Alder加合物，就可以设想将呋喃乙炔锂区域和立体选择性地加成到顺式十氢林体系的一个羰基上。单甲素B全合成的下一步是转化为反式十氢萘体系，然后是阳离子或自由基脱氧，然后是烷基酸内酯。由于与脱氧相关的一个潜在问题是丙叉处立体声信息的丢失，因此也建议首先进行内酯化。那么，结构上更刚性的化合物的脱氧应该不会影响立体声信息。为了准备进一步的合成困难，提出了一种替代的内酯化策略，包括减少炔丙基，然后用甲酯进行硼氢化和内酯化得到的醇。最后，单胞菌素B的最后一步是Lou等人进行的光诱导的[2+2]环加成反应。进行了一些初步的研究，在单抗B存在的情况下，通过Hartwig硅烷化的方法进行后期C-H官能化，应该得到单抗A。因此，单抗B的羰基应该以SmI2为还原剂，立体选择性地转化为羟基。在随后的羟基硅烷化后，加入罗丹明(Xantphos)应该会给氧硅烷提供δ-位置上的甲基。随后的弗莱明-塔毛氧化反应生成δ-羟基化化合物。最后，通过Swern氧化、Pinnick氧化和酯化反应合成单胞菌素A。

The total synthesis of natural products (secondary metabolites) still remains an ongoing challenge and important part of organic chemistry, as natural products and their derivatives can often be used to identify new drugs or drug candidates. In order to accomplish the synthesis of mostly complex target frameworks, one typically relies on well-established reactions and methods. However, to tackle potential synthetic hardships or to circumvent a lack of existing approaches, new methods must be developed.One main class of plant secondary metabolites are terpenoids, some of which also possess significant biological activity. In 2015 Lou et al. reported two novel labdane-type diterpenoids, haplomintrins A and B, which they discovered from the Chinese liverwort Haplomitrium mnioides. The main objective of the present research proposal is to accomplish the first enantioselective total synthesis of haplomintrins A and B. In this vein, it is planned to carry out an enantioselective quinone Diels-Alder reaction as key step, using literature-known chiral catalysts. In addition, it should be tested whether a Nakada-type β-keto imide enables an improved chiral induction of copper bis(oxazoline) complexes, especially if the known chiral catalyst systems fail in this challenging quinone Diels-Alder reaction. With the Diels-Alder adduct in hand, a regio- and stereoselective addition of lithium furylacetylene to one of the carbonyl groups of the cis-decalin system is envisioned. The next step in the total synthesis of haplomitrin B is the transformation into the trans-decalin system, followed by cationic or radical deoxygenation and a subsequent alkynoic acid lactonization. Since one potential problem associated with the deoxygenation is the loss of stereo information at the propargylic position, it is also proposed to carry out the lactonization first. Then the deoxygenation of the structurally more rigid compound should not influence the stereo information. In order to prepare for further synthetic difficulties an alternative lactonization strategy is proposed involving a reduction of the propargyl group, followed by a hydroboration and lactonization of the resulting alcohol with the methylester. Finally, the last step toward haplomintrin B is a photoinduced [2+2] cycloaddition for which Lou et al. conducted some preliminary studies.With haplomintrin B in hand, a late-stage C–H functionalization by means of a Hartwig silylation should lead to haplomintrin A. Therefore, the carbonyl group of haplomintrin B should be stereoselectively converted to a hydroxy group using SmI2 as reducing agent. After subsequent silylation of the hydroxy group, the addition of RhCl(Xantphos) should provide the oxasilolane with the methyl group in δ-position. The subsequent Fleming-Tamao oxidation then leads to the δ-hydroxylated compound. Finally, a sequence of Swern oxidation, Pinnick oxidation and esterification should furnish haplomintrin A.